E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Pulmonary Arterial Hypertension |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 7.0 |
E.1.2 | Level | low |
E.1.2 | Classification code | 10037400 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The primary objective of this study is to evaluate the incidence of increased serum aminotransferase concentrations in subjects who have previously discontinued ERA therapy (bosentan or sitaxsentan) due to serum aminotransferase abnormalities. |
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E.2.2 | Secondary objectives of the trial |
The secondary objectives of this study are to evaluate the safety, tolerability, and efficacy of ambrisentan in this patient population. |
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E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
E.3 | Principal inclusion criteria |
1. Subject must be between 12 and 75 years of age 2. Subject must have a current diagnosis of IPAH, FPAH or PAH associated with: a. Collagen vascular disease(e.g., mixed connective tissue disease, CREST syndrome, systemic sclerosis, overlap syndrome, or systemic lupus erythematosus) b. Congenital systemic-to pulmonary shunts(repaired atrial septal defects, repaired ventricular septal defects, repaired patent ductus arteriosus greater than one year post-operative, or unrepaired secundum atrial septal defect with resting arterial oxygen saturation greater than 88%)c. Anorexigen used. HIV infection 3. Subject must have previously discontinued bosentan or sitaxsentan therapy due to serumaminotransferase (ALT and/or AST) concentrations >3xULN 4. Subject must have normal (<1xULN) serum aminotransferase concentrations at the Screening Visit 5. Subject must walk a distance of at least 150 meters during the 6MWT at the Screening Visit 6. Subject receiving sildenafil for PAH must be on stable therapy for at least 4 weeks prior to screening 7. Subject receiving a clinically approved prostanoid (epoprostenol, treprostinil, iloprost) must be on stable therapy for at least 4 weeks prior to screening 8. Subject with a diagnosis of HIV must have stable disease status during the Screening Period.Stable HIV status is defined as: a. No addition of medications for treatment of HIV in the last 2 months b. No active opportunistic infection during the Screening Period c. No hospitalizations due to HIV within the past 4 weeks 9. Female subject of childbearing potential must have a negative serum pregnancy test at the Screening Visit and a negative urine pregnancy test at the Randomization Visit. Female subject who is surgically sterile or post-menopausal for at least 2 years is not considered to be of childbearing potential 10. Female subject of childbearing potential must agree to use a reliable double barrier method ofcontraception until study completion and for at least 4 weeks following their final study visit. A reliable double barrier method of contraception is considered to be a combination of TWO of the following: birth control pills/ implants/ injections, intrauterine devices, spermicide, diaphragms, or condoms 11. Male subject must be informed of the potential risks of testicular tubular atrophy and infertilityassociated with taking ambrisentan and queried regarding his understanding of the potential risks as described in the Informed Consent Form (ICF)12. Subject must be competent to understand the information given in the Institutional Review Board (IRB) or Independent Ethics Committee (IEC) approved ICF and must sign the form prior to the initiation of any study procedures |
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E.4 | Principal exclusion criteria |
1. Subject with PAH due to or associated with coronary artery disease, left heart disease, interstitial lung disease, chronic obstructive pulmonary disease, veno-occlusive disease, chronic thromboticand/or embolic disease, or sleep apnea 2. Subject with portopulmonary hypertension 3. Subject who has, as measured by historical pulmonary function tests: a. Total lung capacity (TLC) <70% of predicted normal or b. Forced expiratory volume in one second (FEV1) <65% of predicted normal 4. Subject who has : a. A hemoglobin concentration <10 g/dl at the Screening Visit or b. A hematocrit <30% at the Screening Visit 5. Subject with or without supplemental oxygen, who has a resting arterial oxygen saturation (SaO₂) <90 % as measured by pulse oximetry at the Screening Visit 6. Subject who has a history of malignancies within the past 5 years, with the exception of basal cell carcinoma of the skin or in situ carcinoma of the cervix 7. Subject with cardiovascular, liver, renal, hematologic, gastrointestinal, immunologic, endocrine, metabolic, or central nervous system disease that, in the opinion of the investigator, may adversely affect the safety of the subject and / or efficacy of ambrisentan or severely limit the lifespan of the subject 8. Female subject who is pregnant or breastfeeding 9. Subject who has demonstrated non-compliance with previous medical regimens 10. Subject who has a recent history of abusing alcohol or illicit drugs 11. Subject who has participated in a clinical study involving another investigational drug or device within 4 weeks before the Screening Visit |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint of this study is the incidence of confirmed serum aminotransferase concentrations >3xULN during 12 weeks of ambrisentan therapy that are related to ambrisentan and resulted in discontinuation of drug |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Information not present in EudraCT |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Information not present in EudraCT |
E.8.1.3 | Single blind | Information not present in EudraCT |
E.8.1.4 | Double blind | Information not present in EudraCT |
E.8.1.5 | Parallel group | Information not present in EudraCT |
E.8.1.6 | Cross over | Information not present in EudraCT |
E.8.1.7 | Other | Information not present in EudraCT |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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E.8.7 | Trial has a data monitoring committee | Information not present in EudraCT |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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Last visit of the last patient: Approximately May 2007 |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | |
E.8.9.1 | In the Member State concerned months | 20 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial months | 20 |